Objective
We sought to investigate the preschool neurodevelopmental outcomes of children following fetal myelomeningocele (fMMC) surgery.
Study Design
Prior to the Management of Myelomeningocele Study trial, 54 children underwent fMMC closure at our institution. Thirty (56%) returned at 5 years of age for standardized neurocognitive examination. Scores were grouped as high-average, average, mildly delayed, and severely delayed by SD intervals.
Results
Mean verbal intelligence quotient (VIQ), performance intelligence quotient (PIQ), and full intelligence quotient (FIQ) scores were within normal population range. High-average or average scores for VIQ, PIQ, FIQ, and processing speed were found in 93%, 90%, 90%, and 60%, respectively. Mean FIQ and processing speed of nonshunted children were significantly higher than for those who required shunt placement ( P = .02 and P = .01, respectively). Mean VIQ and PIQ tended to be higher in nonshunted fMMC children ( P = .05).
Conclusion
The majority of fMMC children in this highly selective population had average preschool neurodevelopmental scores. fMMC children who did not require shunt placement were more likely to have better scores.
Myelomeningocele (MMC) is a devastating congenital malformation with complex physical and neurodevelopmental sequelae that affects approximately 1 in every 2000 live births. MMC is characterized by defective fusion of the caudal neural tube and exposure of the meninges and neural tissue to the intrauterine environment. Depending on the level of neural tube defect, MMC results in variable degrees of lower extremity motor and sensory deficits, fecal and urinary incontinence, and sexual dysfunction. In addition to the spinal cord dysfunction, significant problems in MMC arise from hydrocephalus and hindbrain herniation as part of the Chiari II malformation. The incidence of hydrocephalus associated with MMC ranges between 70-90% and the children are usually shunt dependent for life. Hydrocephalus adversely affects intellectual outcome and results in late morbidity and mortality caused by shunt malfunction or infection. Generally, children with MMC are at increased risk for neurocognitive impairments, poor school achievement, social challenges, language deficits, and visual motor integration (VMI).
Prior to 1997, fetal surgical intervention was considered only for fetuses with life-threatening anomalies. However, the severe morbidity and significant mortality associated with MMC combined with compelling experimental evidence in animal models that demonstrates the neurological deficits in MMC are acquired early in fetal life and progress in severity throughout gestation led to consideration of prenatal intervention for MMC. Early clinical experience in human beings suggests that ongoing damage to the spinal cord might be alleviated by in utero closure and that fetal intervention potentially improves hindbrain herniation, ventriculoperitoneal shunt rate, and neurofunctional outcome.
We recently reported on short-term neurodevelopmental outcomes of children who underwent fetal MMC (fMMC) surgery at our institution. We found that at 2 years of age approximately two thirds of fMMC children had cognitive language and personal social skills in the low-average to average range. Despite these promising initial results it is currently unknown whether fMMC closure impacts on long-term cognitive and developmental outcomes given the fact that neurodevelopmental skills during early childhood (<3 years) may not be necessarily predictive of outcome in later life. It is possible that the neurodevelopmental deficits identified in our previous study were transient or, conversely, greater deficits may emerge over time. We have continued to follow up this population of children who underwent fMMC surgery prior to the National Institutes of Health (NIH)-sponsored Management of MMC Study (MOMS) trial to investigate preschool neurodevelopmental and cognitive performance.
Materials and Methods
Patient population
This study was approved by the Committee for Protection of Human Subjects Institutional Review Board (IRB# 2000-11-2081). From January 1998 through February 2003, 58 patients met our inclusion criteria ( Table 1 ) and underwent fMMC closure. All infants were subsequently delivered by cesarean section and received neonatal care at our institution. Details of the preoperative evaluation, surgical approach, and postnatal management have been described previously. Data collected from maternal prenatal charts, postnatal hospital charts, and follow-up records included gestational age at fetal intervention, anatomical lesion level, and clinical outcomes. Operative reports of shunt placement, if performed, were reviewed to determine timing and indications for shunt placement. Neurosurgical criteria for ventriculoperitoneal shunt placement have been previously described. Families were asked to return for follow-up at 1, 2, 3, and 5 years of adjusted age. Each visit included evaluations by a pediatrician, physical therapist, developmental psychologist, radiologist, neurosurgeon, and urologist. Neurodevelopmental testing was administered by either a trained psychologist or psychometrist, supervised by a pediatric psychologist (M.G.). The neurodevelopmental outcome data from their follow-up visit form the basis of this study.
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Neurodevelopmental assessment at 1, 2, and 3 years of age
The protocol for the neurodevelopmental assessment has been described elsewhere. Briefly, development was assessed by the Bayley Scales of Infant Development (BSID), 2nd edition, and the Preschool Language Scales-III (PLS) for cognitive development. The BSID is a well-standardized assessment measure for children from birth-3 years of age that generates 2 separate scores. The Mental Developmental Index (MDI) evaluates cognition, language, memory, problem solving, and social skills, and the Psychomotor Developmental Index assesses fine and gross motor skills. The PLS is a standardized assessment of speech and language, and consists of PLS-EXP (expressive) that evaluates use of expressive language and PLS-REC (receptive) that assesses comprehension of language. Both the BSID and PLS yield scores that are normalized to a mean of 100 ± 15. Therefore, a score of ≤70 is >2SD below the mean. Scores were grouped as average, mildly delayed, and severely delayed by SD intervals (115-85, 71-84, <70).
Neurodevelopmental assessment at 5 years of age
Cognitive testing
The Wechsler Preschool and Primary Scale of Intelligence, 3rd Edition (WPPSI-III), was administered to assess cognitive function. The WPPSI-III is a widely used, standardized assessment tool shown to be both valid and reliable. The scales are comprised of 10 verbal and performance subtests and yield verbal intelligence quotient (VIQ), performance intelligence quotient (PIQ), full intelligence quotient (FIQ), and processing speed (PS) scores (expected mean: 100 ± 15). Scores were grouped as above average, average, mildly delayed, and severely delayed by SD intervals (≥116, 115-85, 71-84, <70). The Vineland adaptive behavior scale was administered to assess cognitive function in those children whose delays prevented completion of WPPSI-III testing.
Achievement testing
fMMC children were evaluated with the Woodcock-Johnson Psychoeducational Battery-Revised that evaluates academic performance in reading (letter identification and passage comprehension) and math (calculation and applied problems) that are scaled with a mean 100 ± 15.
Tests of VMI
The Beery-Buktenica Developmental Test of VMI was used to assess visual spatial and VMI ability (mean, 100 ± 15). The test involves copying of geometric forms and is designed to identify potential learning problems.
Test of Differential Abilities Scales
The test of Differential Abilities Scales (DAS) is a standardized intelligence test for assessing general verbal and nonverbal functioning. Scores are reported in form of a t score. The average t score is 50 ± 10.
Statistical analysis
Descriptive statistics, 2-sided t test, and median test were used for statistical comparison to evaluate the overall clinical and early neurocognitive outcome between fMMC survivors who returned for serial follow-up evaluation and those who did not return.
To evaluate the neurodevelopmental outcome, fMMC children who returned for follow-up were divided into 2 groups: nonshunted vs shunted. The 2-sided t test, median test, and logistic regression analysis were used for statistical comparisons as appropriate. P < .05 was considered statistically significant. All statistical tests were performed using a statistical software package (JMP, version 7.0; SAS Corp, Cary, NC).
Results
Patient population
Prior to the National Institute of Child Health and Human Development-MOMS trial, 58 patients underwent fMMC closure at our institution. All fMMC children were delivered ≤36-37 weeks of gestation because of preterm rupture of membranes, preterm labor, or the obstetrical risks associated with the maternal hysterotomy and their overall clinical outcome has been extensively described elsewhere. Four pregnancies were lost due to complications of severe prematurity following delivery for uncontrolled preterm labor at 25, 26, 27, and 27 weeks of gestation, respectively. Overall neonatal survival following fMMC surgery was 93%.
Forty-nine of the 54 (91%) survivors returned at least once for detailed neurodevelopmental assessment during the first 5 years of life. Overall, 37 (68%) returned for follow-up evaluation at 1 year, 30 (56%) at 2 years, 29 (54%) at 3 years, and 30 (56%) at 5 years. Baseline characteristics and fetal surgery details of fMMC children who returned and those who did not return for detailed assessment at 5 years of age are summarized in Table 2 . There were no differences in time of fetal surgical intervention, MMC lesion level, degree of ventriculomegaly progression, incidence of ventriculoperitoneal shunt placement, and overall ambulatory status between groups. However, mean birthweight and mean gestational age at delivery were statistically significantly lower in fMMC children who did not return compared to those who did return.
| Demographic | All fMMC children (n = 54) | fMMC children evaluated at 5 y (n = 30) | fMMC children who did not return (n = 24) | P value |
|---|---|---|---|---|
| GA at fetal surgery (wk, mean ± SD) | 23.1 ± 1.4 | 23.0 ± 1.1 | 23.3 ± 1.6 | .46 |
| GA at delivery (wk, mean ± SD) | 34.7 ± 2.5 | 35.4 ± 1.8 | 33.9 ± 2.9 | .03 |
| Birthweight (g, mean ± SD) | 2482.6 ± 586.5 | 2689.7 ± 479.3 | 2223.9 ± 614.2 | < .001 |
| Median Apgar score at 1 min (range) | 8 (1-9) | 8 (1-9) | 8 (2-9) | .91 |
| Median Apgar score at 5 min (range) | 9 (6-10) | 9 (6-10) | 9 (7-9) | .28 |
| Maximum prenatal VM (mean ± SD) | 11.1 ± 2.4 | 11.2 ± 2.5 | 11.1 ± 2.2 | .58 |
| Maximum postnatal VM (mean ± SD) | 16.1 ± 4.2 | 16.5 ± 4.1 | 15.8 ± 4.3 | .23 |
| Increase in lateral ventricular width (mean ± SD) | 4.9 ± 2.9 | 5.3 ± 3.1 | 4.9 ± 2.6 | .19 |
| VP shunt placement for symptomatic VM | 26 (48%) | 14 (47%) | 12 (50%) | .46 |
| Age at shunt placement (mo, mean ± SD) | 5.4 ± 2.9 | 4.9 ± 2.8 | 6.1 ± 3.1 | .32 |
| Median level of lesion (range) | L4 (T8-S1) | L4 (T12-S1) | L4 (T8-S1) | .45 |
| Ambulatory status at age 5 y | .66 | |||
| Independent | 37 (69%) | 22 (73%) | 15 (62%) | |
| Assisted walking | 13 (24%) | 6 (20%) | 7 (30%) | |
| Wheelchair dependent | 4 (7%) | 2 (7%) | 2 (8%) |
Neurodevelopmental assessment <3 years of age
To evaluate whether children who returned serially and those who did not had different early neurodevelopmental outcomes, comparisons were made among the mean MDI, Psychomotor Developmental Index, PLS-EXP, and PLS-REC scores at the latest available evaluation of children who only returned for their 1-, 2-, or 3-year assessment and the 1-, 2-, or 3-year scores of fMMC children who underwent preschool neurodevelopmental assessment at 5 years of age. As demonstrated in Table 3 , mean neurodevelopmental scores were similar between groups, suggesting that early neurodevelopmental outcomes of fMMC children who returned for the 5-year evaluation were similar to those who did not return.
| Variable | fMMC children evaluated at 5 y | fMMC children who did not return | P value |
|---|---|---|---|
| 12 mo MDI | 87.0 ± 15.5 (92; 50–107) | 90.1 ± 13.2 (90; 58–107) | .52 |
| 12 mo PDI | 56.7 ± 9.2 (54; 50–88) | 56.1 ± 6.2 (57; 50–67) | .81 |
| 12 mo PLS-EXP | 87.4 ± 14.3 (84; 50–113) | 90.2 ± 14.3 (85; 71–113) | .58 |
| 12 mo PLS-REC | 84.5 ± 12.9 (85; 50–119) | 94.5 ± 14.1 (89; 79–121) | .05 |
| 24 mo MDI | 91.5 ± 18.6 (96; 50–112) | 94.6 ± 13.0 (94; 72–118) | .60 |
| 24 mo PDI | 58.1 ± 11.5 (52; 50–88) | 57.6 ± 12.5 (50; 50–87) | .92 |
| 24 mo PLS-EXP | 87.5 ± 19.7 (97; 50–117) | 93.6 ± 10.0 (94; 77–108) | .78 |
| 24 mo PLS-REC | 92.8 ± 21.0 (92; 50–135) | 90.5 ± 13.0 (89; 71–113) | .26 |
| 36 mo MDI | 92.7 ± 16.2 (97; 50–114) | 86.1 ± 18.1 (95; 54–103) | .41 |
| 36 mo PDI | 66.0 ± 14.9 (66; 50–97) | 61.9 ± 12.5 (63; 50–82) | .47 |
| 36 mo PLS-EXP | 94.7 ± 17.7 (97; 50–133) | 97.0 ± 9.8 (98; 84–111) | .68 |
| 36 mo PLS-REC | 100.6 ± 20.3 (102; 50–137) | 97.0 ± 14.1 (103; 81–112) | .65 |
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